In order for our site to display correctly you will need a newer version of your web browser.

Please note that this is not intended to be an exhaustive list of browsers that support web standards, nor a test of browser compliance, nor a side-by-side comparison of various manufacturers’ browsers.

Related Topics

Revealing the Secrets of the Genome

by Elizabeth Jane Walker

Scientists sifting through the vast expanse of data from the Pediatric Cancer Genome Project make discoveries that may lead to cures for childhood cancer.

With tiny trowels and delicate brushes, archaeologists sift through layer upon layer of sand, dirt or silt in their quest to unearth artifacts and better understand the past. With dedication, meticulous attention to detail and a little luck, the workers reveal long-buried secrets or fabulous treasures. But the greatest treasure for mankind is hidden inside each of us—the human genome. For children with cancer, the genome’s secrets hold the keys to health and hope.

About two-and-a-half years ago, scientists at St. Jude Children’s Research Hospital and Washington University School of Medicine in St. Louis joined forces on an expedition to explore the multilayered pediatric cancer genome. Like archaeologists, these researchers hope to uncover secrets that have eluded scientists for generations.

Investigators in the St. Jude – Washington University Pediatric Cancer Genome Project have already begun making exciting discoveries. The papers published thus far have provided the global scientific community with astounding details about cancers of the brain/nervous system, eye and blood. Researchers hope the findings will help them devise more effective ways to treat these diseases.

“The genome project is generating new insights into the genetic alterations that underlie some of the most aggressive childhood cancers,” says James Downing, MD, St. Jude deputy director, scientific director and site leader of the Pediatric Cancer Genome Project. “Those discoveries are pointing us toward new therapeutic options for children with these cancers.”

Tools of the trade

Scientists working with the Pediatric Cancer Genome Project are exploring uncharted territory. The team is sequencing the entire genomes of both normal and cancer cells from 600 childhood cancer patients. By comparing differences in the DNA, scientists can identify genetic mistakes that lead to cancer.

Soon after the project began, St. Jude computational biologists realized they needed a new tool to pinpoint certain cancer-causing mutations that occur within the 3 billion base pairs of DNA in the human genome. Because such a tool did not exist, the scientists created one of their own.

Called Clipping Reveals Structure, or CREST, the computational method offered higher precision than other strategies for finding structural variations, which often involve chromosomal rearrangements or insertion or deletion of genetic material.

“Other tools missed up to 60 to 70 percent of structural rearrangements in tumors,” explains Jinghui Zhang, PhD, the Pediatric Cancer Genome Project’s lead St. Jude computational biologist. The new method created by Zhang and her colleagues is a boon to scientists worldwide who are combing through the vast sets of data in search of genomic treasure.

In January of 2012, top-tier journals began publishing initial findings from the project. The first papers appeared in such prestigious publications as Nature, Nature Genetics, Nature Methods and theJournal of the American Medical Association.

A rare subtype of leukemia

The initial findings emerging from the Pediatric Cancer Genome Project offer hope to children who face overwhelming odds. One such study involves a rare and often deadly form of leukemia.

Although the vast majority of patients with acute lymphoblastic leukemia (ALL) enjoy long-term survival, children with one particular subtype have a poor prognosis. Sixty to 70 percent of patients with early T-cell precursor ALL (ETP-ALL) fail to respond to therapy and succumb to their disease.

Researchers wanted to find out why that happens.

The rare subtype of ALL was included in the Pediatric Cancer Genome Project because the disease was poorly understood and because the outcomes were so devastating. After sequencing genomes of this subtype, the researchers were excited to identify mutations unique to ETP-ALL. This kind of cancer appears to have more in common with acute myeloid leukemia (AML) than with other subtypes of ALL. The findings suggest that children with ETP-ALL may respond better to drugs that have been traditionally used to treat AML.

Work is already underway to develop laboratory models of human ETP-ALL and to use those models to identify AML drugs that may benefit children with the disease.

“We don’t have a definitive answer of what the best treatment will be, but we have a number of very important new options,” says Charles Mullighan, MD, MBBS, of St. Jude Pathology.

“We’re constantly reminded about why we’re doing this work,” Mullighan adds. “Every day we see children and families who are affected by these terrible diseases. It’s strong motivation to do work that will provide important basic scientific insights, ultimately benefiting patients and improving the outcome of treatment.”

Scientists worldwide turned their eyes to St. Jude when the initial paper was published.

“This is the first of a series of important discoveries on the genomic basis of childhood cancers that are emerging from the Pediatric Cancer Genome Project, which is on schedule to fully sequence 600 pediatric cancer genomes by 2013,” announced Dr. William E. Evans, St. Jude director and CEO.

An aggressive form of eye cancer

Illustrating the depth and breadth of the project, other findings soon followed in a spectrum of diseases. For instance, researchers studying the childhood eye cancer retinoblastoma identified the mechanism responsible for its aggressive nature. Retinoblastoma tumors also grow faster than other kinds of tumors. Although 95 percent of children with this disease survive with early detection, many must undergo radiation treatments or eye removal. In developing countries, up to half of children with advanced retinoblastoma die of their disease.

Scientists linked a mutation in the RB1 gene with abnormal activity in other genes, including the SYK gene, which is not normally expressed in the eye. Researchers checking SYK protein levels in normal and cancerous tissues found high levels of the protein in every retinoblastoma tumor sample but not in the normal eye.

“I never, in a million years, would have thought of this gene had we not discovered it through the genome project,” says Michael Dyer, PhD, of St. Jude Developmental Neurobiology.

Required for normal blood development, SYK has been linked to other cancers. Drugs targeting the SYK protein are already in clinical trials for adults with leukemia and rheumatoid arthritis. Dyer and his colleagues are working on an SYK inhibitor that can be delivered directly into the eye. The researchers have found that the drug is effective at killing retinoblastoma cells in the lab, and they hope to move it into Phase I studies soon.

New brain tumor discoveries

Another Pediatric Cancer Genome Project study sheds light on a cancer with one of the worst possible prognoses. More than 90 percent of children with a brain tumor known as diffuse intrinsic pontine glioma (DIPG) die within two years of diagnosis. There are no proven therapies for this aggressive tumor, which cannot be surgically removed because of its location in the brain stem.

“We didn’t really know what to expect when we sequenced the whole genome,” admits Suzanne Baker, PhD, co-leader of the Neurobiology and Brain Tumor Program. “This was an ideal tumor type for sequencing because so little is known about the tumor and there is such a great opportunity to improve outcome for these patients.”

Baker and her colleagues were astounded to discover that 78 percent of the DIPG samples they sequenced exhibited a specific mutation that had never before been identified in other types of human cancer.

“That’s a very exciting finding,” Baker says. “These mutations are found in the tumor DNA and not in the normal DNA from the same individual. That tells us the mutations give the tumor cells a selective growth advantage. This is important in turning a normal cell into a tumor cell.

“By helping us understand what goes wrong in the cell to make these tumors, the data may suggest new therapeutic approaches that would counteract the effects of this mutation.”

Cancer of the nervous system

The genome project is also revealing why the same kind of cancer may endanger children of varying ages in drastically different ways. For example, if an infant, an older child and a teenager have the exact stage of neuroblastoma, a cancer of the nervous system, the patients will likely have dramatically different outcomes, depending on their ages. The survival rate for infants is 88 percent, with the rate plunging to 49 percent for children ages 18 months to 11 years. Only about 10 percent of patients 12 and older become long-term survivors.

“These patients tend to have an indolent clinical course characterized by multiple recurrences of the disease or by disease that is chronic and persistent,” explains Alberto Pappo, MD, director of the St. Jude Solid Tumor Division.

Why do teens and young adults with this cancer of the nervous system have such grim prognoses? Using whole-genome sequencing, Pediatric Cancer Genome Project investigators uncovered a possible answer.

“What we found was really striking and surprising,” Dyer says. “We identified a mutation that tended to only show up in those older patients who have a much worse outcome. The mutation was absent from the very young patients.”

The older patients tended to have mutations in a gene called ATRX, which has been linked to cancers of the pancreas, kidney and ovaries. “This was a known cancer gene, but nothing was known about it in neuroblastoma,” Dyer says. Scientists found that ATRX was mutated only in children ages 5 and older, with the alterations occurring more frequently in older patients. None of the infants with neuroblastoma had the mutation.

Scientists believe these findings may indicate a new subtype of neuroblastoma that affects older children and young adults. St. Jude investigators are currently screening the hospital’s library of federally approved drugs looking for ones that demonstrate activity against cells with the mutation. Investigators also hope to use information gleaned from this study to develop a screening test and to someday be able to reprogram the ATRX gene, thus altering the cancer cells.

Mullighan predicts that the discoveries made thus far are only the first of many to emerge from the Pediatric Cancer Genome Project.

“In just a couple of years, we’ve made major biological and clinical hits,” he says. “That’s pretty impressive.”